Discovery and chemical optimisation of a Potent, Bi-cyclic (Bicycle®) Antimicrobial Inhibitor of Escherichia coli PBP3
crossref(2024)
摘要
Penicillin binding proteins (PBPs) are well validated antimicrobial targets, but the prevalence of β-lactamase driven resistance and, more rarely, target-based mutations, necessitates new classes of PBP-targeting drugs. Here we describe the discovery and optimisation of novel, bicyclic peptide (Bicycle®) inhibitors of E. coli PBP3 ( Ec PBP3) using a proprietary phage display platform, and their conjugation to linear antimicrobial peptides to confer outer membrane permeation. These molecules exhibited high-affinity binding to E. coli PBP3 and a viable spectrum of killing activity against clinically relevant species of the Enterobacterales. X-ray crystallography was used to explore the mode of binding to PBP3, enabling increased target affinity and improvement of in vitro stability. These compounds bind to the transpeptidase active site cleft of PBP3 and represent a novel non-β-lactam chemical class of high affinity, non-covalent penicillin binding protein inhibitors.
### Competing Interest Statement
The authors declare the following competing financial interest(s): C.E.R., C.K., H.N., K.v.R., M.J.S., N.L., N.B., S.J.S, T.T.M., and P.B. are shareholders and/or share option holders in Bicycle Therapeutics plc, the parent company of BicycleTx Ltd.
* caMHB
: cation-adjusted Mueller Hinton broth
Cbg
: cyclobutylglycine
EcPBP3
: E. coli PBP3
EDC
: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
FP
: fluorescence polarisation
HArg
: homoarginine
HPhe
: homophenylalanine
MHB
: Mueller Hinton broth
MIC
: minimal inhibitory concentration
MOPS
: 3-morpholin-4-ylpropane-1-sulfonic acid
NB
: no binding
NHS
: N-hydroxy succinimide
NT
: not tested
SPR
: surface plasmon resonance
TATA
: 1,3,5-triacryoyl-1,3,5-triazinane
tBuGly
: tert-butyl-leucine
2FPhe
: 2-fluoro-phenylalanine
2MePhe
: 2-methyl-phenylalanine
2Pal
: 2-pyridylalanine
3FPhe
: 3-fluoro-phenylalanine
3QuinAla
: 3-Quinoyl-L-alanine
4MeOTrp
: 4-methoxytryptophan
4MePhe
: 4-methyl-phenylalanine
4Pal
: 4-pyridylalanine
5FPhe
: pentafluoro-phenylalanine
5MeOTrp
: 5-methoxytryptophan
6ClTrp
: 6-chlorotryptophan
6FlTrp
: 6-fluorotryptophan.
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